Stereoselective construction of the ABC-ring system of fusidane triterpenes via intermolecular/transannular Michael reaction cascade

Article abstract of DOI:10.1016/j.tetlet.2014.01.071

A stereoselective construction of the ABC-ring system of fusidane triterpenes via intermolecular/transannular Michael reaction cascade is described. The substrate, a ten-membered carbocyclic ketone, has been successfully prepared by the Cr-mediated intramolecular alkenylation of the corresponding acyclic compound. The array of functionalities in the product stereoselectively obtained by the cascade reaction is useful for further structural modifications directed toward the total synthesis of fusidane and other triterpenes, and designed molecules intended for studying structure-activity relationships.

Full text of DOI:10.1016/j.tetlet.2014.01.071

Tetrahedron Letters 55 (2014) 1597–1601
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective construction of the ABC-ring system of fusidane
triterpenes via intermolecular/transannular Michael reaction
cascade
⇑
Tomohiro Fujii, Masahisa Nakada
Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective construction of the ABC-ring system of fusidane triterpenes via intermolecular/transan-
nular Michael reaction cascade is described. The substrate, a ten-membered carbocyclic ketone, has been
successfully prepared by the Cr-mediated intramolecular alkenylation of the corresponding acyclic com-
pound. The array of functionalities in the product stereoselectively obtained by the cascade reaction is
useful for further structural modifications directed toward the total synthesis of fusidane and other
triterpenes, and designed molecules intended for studying structure–activity relationships.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 4 December 2013
Revised 9 January 2014
Accepted 20 January 2014
Available online 31 January 2014
Keywords:
Fusidane
Stereoselective
Intermolecular
Transannular
Michael reaction
Fusidane triterpenes are a relatively small family of naturally
occurring steroidal antibiotics.1 To the best of our knowledge, helv-
olic acid (Fig. 1) was the first reported fusidane triterpene, which
was isolated from Aspergillus fumigatus in the early 1940s.2 Helvol-
ic acid was the subject of structural investigation for a considerable
period;3 Okuda and co-workers finally established the molecular
structure.4 Recent biological evaluation of helvolic acid revealed
that it shows antibiotic activities against Escherichia coli, Bacillus
subtilis, and Micrococcus lysodeikticus with MICs of 14.49, 87.92,
H
A
B
C
R
H
H
chair-boat-chair ABC-ring
fusidane
CO2H
OAc
CO2H
H
and 10.99 l
M, respectively,5 but exhibits synergistic effects with
H
HO
erythromycin, penicillin, and tetracycline on multi-drug resistant
OAc
Staphylococcus aureus.6
H
H
Fusidic acid (Fig. 1), isolated from Fusidium coccineum7a,b as well
as other fungal sources,7c,d,8 is the most important member of fusi-
dane family as fusidic acid shows potent effects against staphylo-
cocci, including the methicillin-resistant Staphylococcus aureus
(MRSA), while exhibiting low toxicity and allergic reactions. More-
over, it has little cross-resistance with other clinically used antibi-
otics.9 Furthermore, the global challenge of antimicrobial
resistance has made fusidic acid a renewed antibiotic candidate;
to date, phase 2 clinical trials have finished and the supporting
results proceed to phase 3 studies.10
O
O
HO
H
H
OAc
helvolic acid
fusidic acid
Figure 1. Structures of fusidine, helvolic acid, fusidic acid, and chair-boat-chair
ABC-ring.
Synthetic studies on fusidic acid have been reported owing to
the promising biological activities described above,11 however,
only one formal total synthesis of fusidic acid12 and no synthetic
studies of helvolic acid have been reported. We report herein a
stereoselective intermolecular/transannular Michael reaction cas-
cade to construct the ABC-ring system of fusidane triterpenes.
Fusidane triterpenes comprise a unique chair-boat-chair ABC
tricyclic ring system in their structures (Fig. 1), which differs from
⇑
Corresponding author. Tel.: +81 3 5283 3240; fax: +81 3 5286 3240.
E-mail address: mnakada@waseda.jp (M. Nakada).
http://dx.doi.org/10.1016/j.tetlet.2014.01.071
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

1598
T. Fujii, M. Nakada / Tetrahedron Letters 55 (2014) 1597–1601
O
O
those found in common steroidal terpenes. Although a number of
synthetic strategies have been reported, transannular processes
are particularly effective to construct such polycyclic ring
systems.13 For example, transannular Diels–Alder reactions can
generate a high degree of structural complexity with high che-
mo-, regio-, and diastereoselectivites (which are difficult to achieve
by inter- or intramolecular processes) as the result of conforma-
tional restrictions, as well as entropic activation derived from the
close proximity in the macrocyclic environment.14
Nu
H
Nu
TIPSO
O
TIPSO
O
O
H
H
4
5
The transannular Diels–Alder reaction was considered for the
synthesis of the unique chair-boat-chair ABC tricyclic ring system
in fusidane triterpenes based on the literature precedent.15 Con-
versely, to the best of our knowledge, construction of the
chair-boat-chair tricyclic ring system via the transannular Michael
reaction has never been reported. The array of functional groups in
the products obtained via the transannular Michael reaction is dif-
ferent from those in the products synthesized by the transannular
Diels–Alder reaction. Thus, the product obtained by the intermo-
lecular/transannular Michael reaction16,17c cascade could be a un-
ique synthetic intermediate for the total synthesis of not only
fusidane triterpenes, but also other terpenes in general. We have
been investigating transannular approaches to the synthesis of
polycyclic ring systems,17 and to this end we report the challenging
intermolecular/transannular Michael reaction cascade which
affords the unique tricyclic ring system.
We have recently developed a highly stereoselective Michael
reduction/intramolecular Michael reaction cascade of compound
1E and 1Z using L-Selectride which affords compounds 2 and 3,
respectively (Scheme 1).18 The three contiguous stereogenic cen-
ters in compound 3 (which includes an all-carbon quaternary ste-
reogenic center) correspond to those in the A-ring moiety of
fusidane triterpenes. Our investigation therefore focused on the
analogous intermolecular/transannular Michael reaction cascade,
which is shown as a retrosynthetic analysis in Scheme 2.
Nu
TIPSO
O
H
6
Scheme 2. Planned intermolecular/transannular Michael reaction cascade.
lective. This assumption prompted us to investigate the prepara-
tion of the macrocyclic ketone 6 to examine the cascade reaction.
The preparation of compound 6 was challenging due to the
presence of the ten-membered carbocyclic ring, which are difficult
to synthesize owing to transannular strain, though the four sp2-
hybridized carbons in the ten-membered carbocyclic ring would
relieve the strain in compound 6. We employed the intramolecular
Cr-mediated alkenylation19 to construct the ten-membered carbo-
cyclic ring because the Cr-mediated reaction is a powerful carbon-
carbon bond-forming reaction that proceeds under mild condi-
tions, and moreover, it is compatible with many functional and
protecting groups. However, to the best of our knowledge, no
examples of the formation of a non-bridged ten-membered carbo-
cyclic ring by the Cr-mediated alkenylation have been reported
thus far.20
The transformation of compound 3 to the substrate for the Cr-
mediated reaction was examined. The Horner–Wadsworth–Em-
mons (HWE) reaction of the aldehyde 8 (Scheme 3) with the keto
phosphonate 10 (Scheme 4) was intended as the method of car-
bon-carbon bond elongation. Preparation of the aldehyde 8 com-
menced with the ester exchange reaction of compound 3. The
reaction was performed with benzyl thiol and potassium carbon-
ate, which caused the selective ester exchange of the more reactive
phenyl ester to afford the benzyl thioester, which was then con-
verted to the aldehyde 8 by Fukuyama reduction.21
The less-hindered a-methylene of compound 6, which would be
prepared from compound 3, is expected to be more reactive to-
ward a nucleophile when compared with the internal enone.
Hence, the enolate 5 would be preferentially formed by the
Michael reaction of compound 6, which would undergo the trans-
annular Michael reaction to afford the tricyclic product 4. The ste-
reoselectivity of the transannular Michael reaction would depend
on the difference of the stability of transition states derived from
the enolate 5 when the reaction is kinetically controlled. The con-
formation of enolate 5 changes by some factors such as solvent and
additives. Therefore, the stereoselectivity of the reaction would be
difficult to predict, but the conformation of enolate 5 is restricted
by the ten-membered ring; thereby, the reaction could be stereose-
CO2Ph
BnSH, K2CO3, DMF
CO2Et
TIPSO
70 °C, 4 h, 76%
H
3
CO2Ph
L-Selectride
O
O
R2
–
78 °C
Pd(OAc)2, Et3SiH
TIPSO
SBn
CO2Et
H
R1
sole product
CO2Et
acetone, rt, 5 min
90%
TIPSO
TIPSO
1
2
H
7
H
1E
: R = H, R = CO2Et
1Z : R1 = CO2Et, R2 = H
8
Scheme 3. Preparation of 8.
CO2Ph
CO2Et
CO2Ph
CO2Et
TIPSO
TIPSO
CH3P(O)(OMe)3
n-BuLi , THF
I
I
3
2
THF, HMPA
78% from
P(OMe)2
O
CO2Et
THF/DMF = 1/2
82% from
1Z
1E
O
10
–
78 °C, quant
9
Scheme 1. Highly stereoselective Michael reduction/intramolecular Michael reac-
tion cascade.
Scheme 4. Preparation of 10.

T. Fujii, M. Nakada / Tetrahedron Letters 55 (2014) 1597–1601
1599
Table 1
The HWE reaction of the aldehyde 8 with the keto phosphonate
10 (prepared by reaction of the known compound 922 with lithiat-
ed dimethyl methylphosphonate, Scheme 4), successfully afforded
the enone 11 (Scheme 5). Compound 11 was reduced with DIBAL-H
to afford the diol 12, which was oxidized with Dess–Martin period-
inane (DMP) to afford the keto-aldehyde 13. The intramolecular Cr-
mediated cyclization of compound 13 was attempted because the
enone was hindered owing to the adjacent all-carbon quaternary
stereogenic center; however, only the 6-endo-trig cyclization was
observed.
Intramolecular Cr-mediated alkenylation
MeO
OMe
CrCl2 (15.0 equiv)
NiCl2 (15 mol%)
solvent
I
TIPSO
50 °C, 15 h
H
CHO
17
MeO
O
OMe
OH
Consequently, compound 11 was converted to its dimethyl ace-
tal 15 (Scheme 6), followed by reduction with DIBAL-H to afford
the alcohol 16. Finally, Dess–Martin oxidation of the alcohol 16
afforded the aldehyde 17, the substrate for the Cr-mediated
reaction.
+
TIPSO
TIPSO
OH
H
H
18
14
The intramolecular Cr-mediated reaction of compound 17 was
carried out in DMSO at 50 °C to afford a mixture of the products
18 (36%) and 14 (16%) (Table 1, entry 1). Conversely, the same reac-
tion in a THF/DMF mixture afforded only 14 (entry 2, 70%). The rea-
son for the different results derived from different solvents is not
clear at this stage and further investigation is now underway, but
the concomitant removal of the acetal is beneficial to reducing
the synthetic steps because the subsequent oxidation afforded
the desired bis-enone. Thus, Dess–Martin oxidation of compound
14 afforded the bis-enone 6 (Scheme 7), the substrate for the intra-
molecular Cr-mediated reaction.
Entry
Conditions
Yielda (%)
18
14
1
2
DMSO
THF/DMF = 1/1
36
0
16
70b
a
Isolated yield.
b
a
/b = 1/20.
O
O
DMP, CH2Cl2
rt, 86%
O
TIPSO
OH
TIPSO
O
H
H
H
CO2Et
10, NaH, 1,4-dioxane
14
6
TIPSO
reflux, 68%
H
Scheme 7. Dess–Martin oxidation of 14.
8
OH
O
I
Having prepared compound 6, the intermolecular/transannular
DIBAL-H, CH2Cl2
0 °C, 89%
Michael reaction cascade was investigated. Interestingly, the reac-
tion of compound 6 with L-Selectride afforded no desired products
and the products with the exomethylene were obtained under sev-
eral reaction conditions. The results indicated that the first reaction
took place at the inner enone in a 1,2-reduction manner and the
I
TIPSO
TIPSO
H
H
CO2Et
OH
11
12
O
O
preferential reaction of a-methylene ketone did not proceed. This
DMP, CH2Cl2
rt, 90%
unexpected result prompted us to investigate the reaction with
other nucleophiles.
I
We examined the reaction of compound 6 with thiophenol be-
cause soft nucleophiles tend to undergo Michael addition and the
introduced phenylthiomethyl group can be converted to a methyl
group under the reductive conditions using Raney-Nickel (Table 2).
Moreover, the reaction of thiophenol was expected to preferen-
tially take place at the exomethylene because the reaction of thio-
phenol at the inner enone would suffer from the steric strain
derived from the adjacent all-carbon quaternary center.
Indeed, the products 19 (9%) and 20 (30%) were obtained when
potassium carbonate was used in methanol at 50 °C (entry 1). The
same reaction at 0°C afforded the products 19 (8%) and 20 (54%)
(entry 2), and the reaction with DBU afforded the products 19
(13%) and 20 (73%) (entry 3). The reaction with potassium thio-
phenoxide in methanol at 0 °C afforded only 20 but the yield
was 41% (entry 4). The same reaction in THF at ꢀ78 °C improved
the yield but was 43% (entry 5). Interestingly, the same reaction
in the presence of 18-crown-6 afforded negligible products, even
at room temperature (entry 6).
TIPSO
TIPSO
OH
H
H
CHO
13
14
Scheme 5. Attempted preparation of 14.
O
MeO
H
OMe
CH3C(OMe)3
MeOH, p-TsOH
reflux, 79%
I
I
TIPSO
TIPSO
TIPSO
H
CO2Et
CO2Et
15
11
MeO OMe
MeO OMe
DIBAL-H
CH2Cl2
DMP, Py
CH2Cl2, rt
0 °C
75%
I
I
TIPSO
(2 steps)
H
H
As the intermolecular/transannular Michael reaction cascade is
reportedly initiated by an alkoxide,16c the reaction of compound 6
with alkoxides was examined. The reactions with p-methoxybenzyl
alcohol afforded unidentified products, probably due to undesired
CHO
OH
16
17
Scheme 6. Preparation of 17.

1600
T. Fujii, M. Nakada / Tetrahedron Letters 55 (2014) 1597–1601
Table 2
Intermolecular/transannular Michael reaction cascade of 6 (R0 = TIPS)
O
O
O
R
R
R
+
conditions
R'O
H
H
R'O
H
O
O
R'O
O
H
H
6
19
20
Entry
Reagent (equiv)
Solvent
Temp (°C)
Time (h)
Yielda (%)
19
20
1
2
3
4
5
6
7
8
9
10
11
12
13
14
PhSH (3.0)/K2CO3 (5.0)
PhSH (3.0)/K2CO3 (5.0)
PhSH (3.0)/DBU (5.0)
PhSK (2.0)
MeOH
MeOH
MeOH
MeOH
THF
THF
THF
THF
—
THF
THF
THF
THF/DMF = 1/1
THF
50
0
0
2
3
3
1
1
5
4
4
3
8
8
8
8
8
9
8
13
0
0
tc
0
0
0
0
0
0
0
0
30
54
73
41
43
tc
0
0
0
0
0
0
PhSK (2.0)
ꢀ78
PhSK (2.0)/18-C-6 (10.0)b
PMBOH (2.0)/nBuLi (1.5)
PMBOH (2.0)/K2CO3 (5.0)
AllylOH/K2CO3 (5.0)
p-MeOPhOH/KHMDS (1.5)
p-MeOPhOK (1.5)
rt
ꢀ78
ꢀ78
rt
ꢀ78
rt
p-MeOPhOK (1.5)
p-MeOPhOK (1.5)
p-MeOPhOK (1.5)
50
rt
rt
0
0
0
a
b
c
Isolated yield.
18-C-6: 18-crown-6.
t: trace amount.
O
O
O
O
PhS
H
PhS
H
PhS
SPh
O
a) K2CO3, MeOH
b) DBU, MeOH
c) DBU, THF
H
HO
HO
H
H
O
H
H
O
HO
HO
O
H
TIPSO
TIPSO
O
50 °C, 2 h, NR
H
21
20
19
PhS
Scheme 8. Attempted conversion of 20 to 19.
H
O
O
H
side-reactions such as intramolecular Michael reactions owing to
the relatively high basicity of the alkoxide (entries 7 and 8). The
reaction with allyl alcohol resulted in the same results (entry 9).
The reaction with the less basic p-methoxyphenoxide was at-
tempted; no desired products were formed (entries 10–14).
We examined the transformation of 20 to 19 via the retro-
H
O
SPh
H
22
Figure 2. Selected NOE correlations observed in the NOESY spectra of 21 and 22.
Michael process under several conditions used in Table
2
SPh
O
(Scheme 8). However, no isomerization was observed, indicating
that the cascade process is kinetically controlled but not thermo-
dynamically controlled.
The configuration of the products 19 (R = SPh) and 20 (R = SPh)
was elucidated based on the NOESY spectra of their desilylated
derivatives 21 and 22; the selected NOE correlations are summa-
rized in Figure 2.
The stereoselectivity of the intermolecular/transannular Mi-
chael reaction cascade depends on the transition states of the
transannular Michael reaction because the results summarized in
Scheme 8 indicates that the reaction is kinetically controlled.
Although four transition states TS 1–4 (Figure 3) are possible for
the transannular Michael reaction, TS 2 and TS 4 are highly
strained because the former includes the 1,3-diaxial interaction be-
tween the methyl and phenylthiomethyl groups, and in addition to
that, the 1,3-diaxial interaction derived from the cis-fused decaline
system, and the latter comprises two boat conformations.
Hence, the reaction was surmised to proceed via TS 1 and TS 3
that afford compounds 19 and 20, respectively. TS 3 would be ener-
getically favored because the large 1,3-diaxial interaction in TS 1
SPh
H
TIPSO
TIPSO
TIPSO
TIPSO
H
H
H
O
O
O
TS 1
TS 2
O
H
O
O
O
H
H
H
SPh
SPh
TS 3
TS 4
Figure 3. TS 1, TS 2, TS 3, and TS 4.
would render its energy level higher than that of TS 3. However,
TS 3 includes the energetically unfavorable boat conformation.
Hence, the difference of the stability between TS 1 and TS 3 would

T. Fujii, M. Nakada / Tetrahedron Letters 55 (2014) 1597–1601
1601
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O
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Raney-Ni
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H
H
EtOH
rt, 56%
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O
TIPSO
O
H
H
20
23
(R = SPh)
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Scheme 9. Conversion of 20 (R = SPh) to 23.
be not so large, resulting in the observed preferential formation of
compound 20 with moderate stereoselectivity. It is interesting that
compound 20 was formed as the single isomer in entries 4 and 5
though the yield should be improved. The reason for the high
selectivity is now under investigation.
As compound 20 (R = SPh) was obtained in 73% yield, which is a
reasonable yield for synthetic purpose, removal of the phenylthio
group was examined. The phenylthio group in 20 (R = SPh) was
expectedly removed using Raney-nickel in ethanol to afford com-
pound 23 (56%, not optimized) (Scheme 9), which possesses the
ABC-ring scaffold of fusidanes with correct stereogenic centers
and appropriate functionalities for further transformations re-
quired for the total synthesis of fusidanes. The phenylthiomethyl
group in 20 (R = SPh) would be converted to a formyl group via
Pummerer rearrangement; thereby, an oxygen atom could be
introduced at the same position. Therefore, 20 (R = SPh) could be
a useful intermediate for other natural products, too.
In summary, we have developed an intermolecular/transannu-
lar Michael reaction cascade that could lead to a new stereoselec-
tive approach to the ABC-ring system in fusidane triterpenes. The
substrate, a ten-membered carbocyclic ketone, has been success-
fully prepared by the Cr-mediated intramolecular alkenylation of
the corresponding acyclic compound. The array of functionalities
in the product obtained by the cascade reaction is useful for further
structural modifications directed toward the total synthesis of fusi-
dane and other triterpenes, and designed molecules intended for
studying structure–activity relationships.
12. Dauben, W. G.; Kessel, C. R.; Kishi, M.; Somei, M.; Tada, M.; Guillerm, D. J. Am.
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Acknowledgments
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This work was financially supported in part by the Waseda
University Grant for Special Research Projects, The Grant-in-Aid
for Scientific Research on Innovative Areas ‘Organic Synthesis
based on Reaction Integration, Development of New Methods and
Creation of New Substances’ (No. 2105), and Grants for Excellent
Graduate Schools (Practical Chemical Wisdom), MEXT, Japan.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.01.
071.
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